Long term sustained release pharmaceutical composition containing aqueous suspension of bisphosphonate

ABSTRACT

Pharmaceutical compositions for long-term sustained release of bisphosphonate drugs are provided. In one embodiment, the composition includes an aqueous suspension of a solid which includes a salt of a bisphosphonate drug and a salt of pentavalent phosphorus oxoacid. The compositions can be used to treat a variety of bone diseases, including osteoporosis.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/768,181, filed Jun. 25, 2007, which claims priority to and thebenefit of U.S. Provisional Application Ser. No. 60/876,800, filed onDec. 21, 2006 in the U.S. Patent and Trademark Office, and titled “LONGTERM SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING AQUEOUSSUSPENSION OF BISPHOSPHONATE,” the entire contents of both of which areincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to sterile pharmaceutical compositions forthe long term sustained release of bisphosphonate drugs. Moreparticularly, the present invention relates to long term sustainedrelease formulations of bisphosphonate drugs for the treatment andprevention of osteoporosis and other related bone diseases.

BACKGROUND

Osteoporosis is a bone disease characterized by low bone mass andstructural deterioration of bone tissue, leading to increased bonefragility and susceptibility to fracture, especially in the spine, hipand wrist areas. Osteoporosis is a major public health and economicproblem. According to the US National Osteoporosis Foundation,osteoporosis affects about 44 million Americans. It is estimated that 10million individuals in the US already have the disease and almost 34million more are estimated to have low bone mass, placing them atincreased risk for osteoporosis. Approximately 80% of those affected byosteoporosis are women. Data indicates that one out of every two womenand one in four men over 50 will have an osteoporosis related fracturein their lifetime. However, osteoporosis can strike at any age.Osteoporosis is responsible for more than 1.5 million fracturesannually. The estimated national direct expenditures (hospitals andnursing homes) for osteoporosis and related fractures total about $14billion each year.

Osteoporosis and/or other related bone diseases lower a patient'squality of life, making the prevention and/or treatment of the diseasesan important subject matter. Many alternatives are available to preventand/or treat osteoporosis such as: Estrogen/Hormone Replacement Therapy(ERT/HRT) commercially available under the name Estrace®, Estraderm®,Premarin® etc.; Selective Estrogen Receptor Modulators (SERMs)commercially available under the name Evista®; bisphosphonatescommercially available under the name Fosamax®, Boniva®, Actonel® etc.Other medications are also available such as calcitonin commerciallyavailable under the name Miacalcin®; calcium supplements; vitamin D; andsodium fluoride.

Bisphosphonates appear to be one of the most effective and popularoptions for the prevention and/or treatment of osteoporosis and otherrelated diseases such as Paget's disease, malignant hypercalcemia andmetastatic bone disease, etc. Currently marketed bisphosphonates areavailable for oral or intravenous administration. Oral administration isgenerally favorable due to its ease of administration. However, oraladministration of bisphosphonates is associated with low bioavailabilityand is also known to cause gastrointestinal related side effectsincluding: esophagitis, esophageal ulceration, retrosternal pain, andlocal irritation of the upper gastrointestinal mucosa. In addition,administration of bisphosphonates involves complicated and inconvenientprocedures. Under the best conditions, oral bioavailability ofbisphosphonates like Fosamax®, Boniva® and Actonel® is less than 1%, andbioavailability is even less if the recommendations for administrationare not followed. It is estimated that only about 50% of orally absorbedbisphosphonates reach the therapeutic sites, while the rest is excretedin the urine.

Intravenous (“IV”) administration of bisphosphonates is common for thetreatment of hypercalcemia but is not the normal method ofadministration for the treatment of osteoporosis. Furthermore, IVadministration of bisphosphonates involves complicated and inconvenientadministration procedures and is associated with more adverse effects,such as osteonecrosis of the Jaw (“ONJ”). It has been reported that 97%of ONJ related to bisphosphonate drugs were affiliated with IVadministration. In either administration, the drug reaches its peak in ashort period of time and is cleared out of the system within a couple ofhours.

Due to their poor bioavailability, bisphosphonate drugs need to becontinuously administered for years to be effective in theprevention/treatment of osteoporosis. However, due to their inconvenientadministration requirements and associated side effects, theirapplication for long term prevention and treatment in patients withosteoporosis is challenging and limited.

SUMMARY OF THE INVENTION

According to certain embodiments of the present invention,administration of the bisphosphonate drugs is needed only once everyseveral months, and the side effects of the bisphosphonates aresubstantially reduced or eliminated. As such, some embodiments of thepresent invention provide invaluable long term benefits includingincreased bone mineral density and reduced fractures.

Certain embodiments of the present invention relate to sterilepharmaceutical compositions for the long term sustained release ofbisphosphonate drugs through intramuscular administration. In oneembodiment, the pharmaceutical composition comprises an aqueoussuspension of a bisphosphonate drug. In another embodiment, the presentinvention is directed to a long term sustained release pharmaceuticalcomposition comprising an aqueous suspension of a solid consisting of asalt of a bisphosphonate drug and a salt of pentavalent phosphorusoxoacid. The aqueous suspension of the solid is adapted to release thebisphosphonate drug into the patient over an extended period of time,for example over about two months or longer. The composition is suitablefor intramuscular administration and is useful for the treatment andprevention of osteoporosis and other bone related diseases.

According to one embodiment, the bisphosphonate drug has a generalstructure, in its acid form (bisphosphonic acid) of (HO)₂PO—R—OP(OH)₂,where R can include various groups such that the bisphosphonate includesbut is not limited to, pamidronic acid, alendronic acid, ibandronicacid, risedronic acid; zoledronic acid, and tiludronic acid.

One embodiment of the present invention is directed to a long termsustained release pharmaceutical composition comprising an aqueoussuspension of a salt of a bisphosphonate drug and a salt of pentavalentphosphorus oxoacid, wherein the salts are salts of calcium, zinc,magnesium and combinations thereof. The salts of the bisphosphonatedrugs include, but are not limited to, normal salts, acidic salts, basicsalts and combinations thereof. The salts of the bisphosphonate drugsmay also include anhydrous salts, hydrates and combinations of hydrates.The salts of pentavalent phosphorus oxoacid include, but are not limitedto, normal salts, acidic salts, basic salts and combinations thereof.The salts of pentavalent phosphorus oxoacid may also include phosphates,pyrophosphates, metaphosphates, polyphosphates and combinations thereof.Additionally, the salts of pentavalent phosphorus oxoacid may includeanhydrous salts, hydrates and combinations of hydrates.

Nonlimiting examples of suitable salts of pentavalent phosphorus oxoacidinclude dicalcium phosphate dihydrate, dicalcium phosphate anhydrate,octacalcium phosphate, α-tricalcium phosphate, β-tricalcium phosphate,amorphous calcium phosphate, calcium-deficient hydroxyapatite,hydroxyapatite, and tetracalcium phosphate.

Another embodiment of the present invention is directed to a long termsustained release pharmaceutical composition comprising a solidincluding a salt of a bisphosphonate drug and a salt of pentavalentphosphorus oxoacid, wherein the solid has a solubility in saline of lessthan about 0.05% by weight as bisphosphonic acid. The solid can beamorphous, crystalline (in which it may have a variety of crystalstructures), or a mixture thereof. In one embodiment, the solid has aparticle size of less than about 100 micrometers.

Still another embodiment of the present invention is directed to a longterm sustained release composition in which the solid is suspended in anaqueous medium and has a pH ranging from about 6.0 to about 9.5. Oneaqueous medium for the composition of the present invention is water forinjection, U.S.P.

The sustained release pharmaceutical composition according to oneembodiment may further have a weight ratio of calcium to phosphorusranging from about 0.5 to about 3.0.

The composition according to one embodiment may also include one or moreinactive pharmaceutical excipients. Nonlimiting examples of suitableexcipients include surfactants, suspending agents, dispersing agents,tonicity agents, preservatives, pH buffers, agents for adjusting osmoticpressure, agents for adjusting viscosity, agents for adjusting density,and the like.

Another embodiment of the present invention is directed to a method ofpreparing the composition. Nonlimiting examples of suitable methodsinclude co-precipitation, co-crystallization, diffusion, infiltration,adsorption and the like.

In sum, in one embodiment of the present invention, a sterilepharmaceutical composition comprises an aqueous suspension of abisphosphonate drug for injectable administration. The composition is asolid that includes a bisphosphonate salt and a salt of pentavalentphosphorus oxoacid. The composition is for the sustained release of thebisphosphonate salt. The solid has low solubility, i.e. less than about0.05% in saline by weight and as the bisphosphonic acid.

According to one embodiment, the bisphosphonate drug has a generalstructure, in its acid form (bisphosphonic acid), of

In the Formula, R can have various structures, including anybisphosphonate, including, but not limited to:

-   -   1-hydroxy-4-amino-butylidene (Alendronic acid),    -   1-hydroxy-3-(methylpentylamino)propylidene (Ibandronic acid),    -   1-hydroxy-3-amino-1-propylidene (Pamidronic acid),    -   1-hydroxy-2-(3-pyridinyl)-ethylene (Risedronic acid),    -   4-chloro-phenyl)-thio-methylene (Tiludronic acid)    -   1-hydroxy-2-imidazol-1-yl-ethylene (Zoledronic acid).

In another embodiment, the salts can be salts of calcium, zinc,magnesium and combinations thereof. The salt of the bisphosphonate drugmay be a normal salt, an acidic salt, a basic salt or a combinationthereof. The salt of the bisphosphonate drug may be an anhydrous salt, ahydrate, or a combination of various hydrates of bisphosphonic drugs.The salt of pentavalent phosphorus oxoacid may be a phosphate, apyrophosphate, a metaphosphate, a polyphosphate or a combinationthereof. The salt of pentavalent phosphorus oxoacid can be a normalsalt, an acidic salt, a basic salt or a combination thereof. The salt ofpentavalent phosphorus oxoacid may be an anhydrous salt, a hydrate, or acombination of various hydrates. Nonlimiting examples of suitable saltsof pentavalent phosphorus oxoacid include:

-   -   dicalcium phosphate dihydrate (DCPD), CaHPO₄·2H₂O    -   dicalcium phosphate anhydrate (DCPA), CaHPO₄    -   octacalcium phosphate (OCP), Ca₈(HPO₄)₂(PO₄)₄·5H₂O    -   α-Tricalcium phosphate (α-TCP), α-Ca₃(PO₄)₂    -   β-Tricalcium phosphate (β-TCP), β-Ca₃(PO₄)₂    -   amorphous calcium phosphate (ACP), Ca_(x)(PO₄)_(y)·nH₂O    -   calcium-deficient hydroxyapatite (CDHA),        Ca_(10-x)(HPO₄)_(x)(PO₄)_(6-x)(OH)_(2-x) (x=0˜1)    -   hydroxyapatite (HA), Ca₁₀(PO₄)₆(OH)₂    -   tetracalcium phosphate (TTCP), Ca₄(PO₄)₂O

In one embodiment, the solid can be amorphous or crystalline havingvarious crystal structures, or a mixture thereof.

According to one embodiment, the weight percentage of the salt of thebisphosphonate drug in the composition is less than about 50%. Theweight ratio of calcium to phosphorus in the composition ranges fromabout 0.5 to about 3.0. The average particle size of the compositionranges from about 1 to about 100 micrometers.

In one embodiment, the pharmaceutical aqueous vehicle in the sterilepharmaceutical aqueous suspension of the composition is water forInjection, U.S.P. The pH of the sterile pharmaceutical aqueoussuspension composition for injectable administration ranges from about6.0 to about 9.5.

In another embodiment, the sterile pharmaceutical aqueous suspension ofthe composition may contain various inactive pharmaceutical excipients,such as surfactants, suspending agents, dispersing agents, tonicityagents, preservatives, pH buffers, agents for adjusting osmoticpressure, agents for adjusting viscosity, agents for adjusting density,etc.

The composition can be prepared by any suitable means, including but notlimited to co-precipitation, co-crystallization, diffusion,infiltration, etc.

According to one embodiment, a sterile pharmaceutical aqueous suspensioncomposition for injectable administration of bisphosphonate drugsincludes a solid having a calcium salt of a bisphosphonate drug and acalcium salt of pentavalent phosphorus oxoacid. The composition is forsustained release of a bisphosphonate drug and the aqueous suspension ofthe solid is adapted to release the bisphosphonate drug into the patientover an extended period of time, for example over about two months orlonger. The composition has a low solubility of less than about 0.05% insaline, by weight and as the bisphosphonic acid. The compositioncontains the calcium salt of the bisphosphonate drug in an amount ofabout 50% or less by weight. The particle size of the suspensioncomposition ranges from about 1 to about 100 micrometers. The pH of thesterile pharmaceutical aqueous suspension composition ranges from about6.0 to about 9.5. The weight ratio of calcium and phosphorus in theaqueous suspension ranges from about 0.5 to about 3.0.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other features and advantages of the present inventionwill be better understood by reference to the following detaileddescription when considered in conjunction with the accompanyingdrawings in which:

FIG. 1 is a graph of the solubility of an alendronate calcium-phosphatecalcium complex according to one embodiment of the present inventionbased on the amount of active pharmaceutical ingredient in the complex;

FIG. 2 is a graph comparing rat daily urine excretions over time of analendronate calcium-phosphate calcium complex according to oneembodiment of the present invention and an active prior art control; and

FIG. 3 is a graph of changes in rat bone mineral density over time afteradministration of two different dosages of an alendronatecalcium-phosphate calcium complex according to one embodiment of thepresent invention and a saline placebo.

DETAILED DESCRIPTION OF THE INVENTION

According to one embodiment of the present invention, a sterilepharmaceutical composition comprises an aqueous suspension of abisphosphonate drug. The pharmaceutical composition is a long termsustained release composition comprising an aqueous suspension of asolid including a salt of a bisphosphonate drug and a salt ofpentavalent phosphorus oxoacid. The aqueous suspension of the solid isadapted to release the bisphosphonate drug into the patient over anextended period of time, for example over about two months or longer.The composition is suitable for intramuscular administration and isuseful for the prevention and treatment of osteoporosis and other bonerelated diseases.

Surprisingly, Applicants have discovered that compositions of thepresent invention, namely suspensions of complex salts of bisphosphonicacid, produce significantly lower solubility (approximately 100 to 1000times lower) compared to prior art calcium salts. This allows theformulations of the present invention to exhibit much slower and morelong term sustained release profiles as illustrated in the examplesoutlined below. For example, as noted above, the aqueous suspension ofthe solid is adapted to release the bisphosphonate drug into the patientover an extended period of time, such as over about two months orlonger.

In one embodiment, the bisphosphonate drug may have a general structure,in its acid form (bisphosphonic acid) of (HO)₂PO—R—OP(OH)₂, where R caninclude any group for the bisphosphonate, nonlimiting examples of whichinclude 1-hydroxy-3-amino-1-propylidene (Pamidronic acid),1-hydroxy-4-amino-butylidene (Alendronic acid),1-hydroxy-3-(methylpentylamino)propylidene (Ibandronic acid),1-hydroxy-2-(3-pyridinyl)-ethylene (Risedronicacid),1-hydroxy-2-imidazol-1-yl-ethylene (Zoledronic acid), and(4-chloro-phenyl)-thio-methylene (Tiludronic acid).

According to one embodiment, the present invention is directed to asustained release pharmaceutical composition comprising a solidincluding a salt of a bisphosphonate drug and a salt of pentavalentphosphorus oxoacid. The solid is suspended in an aqueous medium. Thesolid has solubility in saline of less than about 0.05% by weight asbisphosphonic acid. The solid has a particle size of less than about 100micrometers, for example the solid may have a particle size ranging fromabout 10 to about 50 micrometers. The solid may be amorphous,crystalline (having a variety of crystal structures), or a mixturethereof. One nonlimiting example of a suitable aqueous medium is waterfor injection, U.S.P.

Nonlimiting examples of suitable salts for the composition include saltsof calcium, zinc, magnesium and combinations thereof. The salt of thebisphosphonate drug may include, but is not limited to, normal salts,acidic salts, basic salts, anhydrous salts, hydrates and combinationsthereof. The salt of pentavalent phosphorus oxoacid may include, but isnot limited to, normal salts, acidic salts, basic salts, phosphates,pyrophosphates, metaphosphates, polyphosphates, anhydrous salts,hydrates and combinations thereof.

Nonlimiting examples of suitable salts of pentavalent phosphorus oxoacidinclude dicalcium phosphate dihydrate (DCPD), CaHPO₄·2H₂O; dicalciumphosphate anhydrate (DCPA), CaHPO₄; octacalcium phosphate (OCP),Ca₈(HPO₄)₂(PO₄)₄·5H₂O; α-tricalcium phosphate (α-TCP), α-Ca₃(PO₄)₂;β-Tricalcium phosphate (β-TCP), β-Ca₃(PO₄)₂; amorphous calcium phosphate(ACP), Ca_(x)(PO₄)_(y)·nH₂O; calcium-deficient hydroxyapatite (CDHA),Ca_(10-x)(HPO₄)_(x)(PO₄)_(6-x)(OH)_(2-x) (x=0˜1); hydroxyapatite (HA),Ca₁₀(PO₄)₆(OH)₂; and tetracalcium phosphate (TTCP), Ca₄(PO₄)₂O.

According to one embodiment, the composition has a weight ratio ofcalcium to phosphorus ranging from about 0.5 to about 3.0, for example,the weight ratio of calcium to phosphorus may range from about 1.5 to2.5. The pH of the composition may range from about 6.0 to about 9.5,for example, the pH of the composition may range from about 6.5 to about8.5. Optionally, the composition may also contain various inactivepharmaceutical excipients. Nonlimiting examples of suitable excipientsinclude surfactants, suspending agents, dispersing agents, tonicityagents, preservatives, pH buffers, agents for adjusting osmoticpressure, agents for adjusting viscosity, agents for adjusting density,and mixtures thereof.

In one embodiment, the composition is a long term sustained releaseformulation of a solid comprising: (a) a salt of a bisphosphonate drug,and (b) a salt of pentavalent phosphorus oxoacid, wherein the solid issuspended in an aqueous solution to form a suspension. The salt of thebisphosphonate drug is present in the composition in an amount less thanabout 50% by weight, for example, the salt of the bisphosphonate drug ispresent in an amount ranging from about 5 to about 30%. One exemplarysalt for the composition is a calcium salt. The weight ratio of calciumto phosphorus in the composition ranges from about 0.5 to about 3.0, forexample, the weight ratio of calcium to phosphorus may range from about1.5 to about 2.5. The solid has a particle size of less than about 100micrometers, for example, the solid may have a particle size rangingfrom about 10 to about 50 micrometers. The aqueous solution may be waterfor injection, U.S.P. The aqueous suspension may have a pH ranging fromabout 6.0 to about 9.5, for example, the pH may range from about 6.5 toabout 8.5. The aqueous suspension may contain one or more inactivepharmaceutical excipients including, but not limited to, surfactants,suspending agents, dispersing agents, tonicity agents, preservatives, pHbuffers, agents for adjusting osmotic pressure, agents for adjustingviscosity, agents for adjusting density, and the like.

Certain compositions of the present invention provide long termsustained release of bisphosphonate drugs. In addition, certaincompositions avoid various adverse side effects associated with oraladministration of bisphosphonate drugs. The delivered dose of theinventive compositions is much smaller than the oral dose, which hashigh bioavailability, thereby avoiding many of the adverse side effectsassociated with high oral doses. The inventive sustained releasecompositions also substantially eliminate peak doses (over dose) andvalley doses (under dose). The inventive compositions are convenient forpatients and reduce tissue irritation due to their extremely lowsolubility.

As noted above and illustrated in the below examples, certainembodiments of the compositions of the present invention have improvedsustained release profiles compared with prior art compositions. Inparticular, according to one embodiment of the present invention, thecomposition releases an initial bolus of less than about 10%. Theinitial bolus is defined as the amount of the drug released in the firstthree days after administration. For example, one embodiment of thepresent invention releases an initial bolus of about 8% (which is muchlower that the prior art at about 55%), as illustrated in the Examplesbelow.

According to another embodiment of the present invention, thecomposition releases a maximum concentration, or peak amount (denotedCmax), of less than about 10 mcg/day. For example, one embodiment of thepresent invention has a Cmax of about 8 mcg/day, which is much lowerthan the prior art at 74 mcg/day.

In yet another embodiment, the composition releases the peak amount(Cmax) over an extended period of time. The time it takes to releaseCmax is denoted tmax, and according to one embodiment, tmax is greaterthan about 10 days. For example, one embodiment of the present inventionhas a tmax of about 13 days, which is much longer than the prior art at1 day.

According to still another embodiment of the present invention, it takesthe composition an extended period of time to release 50% and 90% of thedrug. The time it takes the composition to release 50% of the drug isdenoted N₅₀, and the time it takes the composition to release 90% of thedrug is denoted N₉₀. According to one embodiment, the composition has aN₅₀ of greater than about 15 days, and a N₉₀ of greater than about 35days. For example, in one embodiment, the composition has a N₅₀ of about16.6 days, and a N₉₀ of about 38.5 days, which are also much longer thanthe prior art, at 2.8 and 9 days respectively.

The compositions of the present invention can be prepared in many ways.In one embodiment, for example, the composition is prepared byco-precipitation. In another embodiment, the composition is prepared byco-crystallization. In yet another embodiment, the composition isprepared by diffusion. In still another embodiment, the composition canbe prepared by infiltration or adsorption. The sustained releasecompositions of the present invention and methods of preparing thecompositions are further illustrated in the following examples, whichare provided for illustrative purposes only, and are not intended tolimit the scope of the present invention.

COMPARATIVE EXAMPLE 1 Preparation of Alendronate Calcium (AC)

For purposes of comparison with certain embodiments of the presentinvention, an alendronate calcium (AC) composition was preparedaccording to this example that does not include a salt of pentavalentphosphorus oxoacid.

2.03 g (6.3 mM) of sodium alendronate trihydrate was dissolved in 60 mLwater. 0.94 g of calcium chloride dihydrate was dissolved in 30 mLwater. Both solutions were cooled to room temperature.

To the alendronate solution, sodium hydroxide and calcium chloridesolutions were simultaneously added to keep the pH of the solution at7.0 until all the calcium chloride solution had been added. Theprecipitate was collected by filtration and washed with water. The solidwas dried in an oven at 120° C. over night to obtain 1.5 g ofalendronate calcium, denoted as Ca_(k)Y (where Y is the Alendronateanion). The mean value of k for the generated alendronate calcium atneutral solution (the pH of human blood) was 1.5+/−0.1. Chemically,Ca_(1.5)Y corresponds to Ca₃Y₂. The solubility of Ca_(1.5)Y in saline,as alendronic acid, was measured as 247 mcg/mL or 0.0247%.

The saline solubility measurement was performed as follows (unlessotherwise described, all solubility of the complex products in salinewere measured using the following procedures): the saline was pHbuffered at pH=7.4. 200 mg of the product was added to 20 mL of thebuffered saline. This solution was stirred at room temperature to reachequilibrium. The supernatant was separated by centrifugation andfiltration through a 0.1 μm filter. The alendronate was measured by highperformance liquid chromatography (HPLC).

EXAMPLE 1 Preparation of Complex (Sosoloid) of AlendronateCalcium-Phosphate Calcium (AC-PC)

Phosphate salt is a commonly used salt of pentavalent phosphorusoxoacid. This example demonstrates the preparation of a complex orsosoloid of Alendronate Calcium-Phosphate Calcium (AC-PC) byco-precipitation according to one embodiment of the present invention.

4.06 g (12.5 mM) of sodium alendronate trihydrate and the same molaramount of monobasic sodium phosphate (anhydrous) 1.5 g (12.5 mM) weredissolved in 160 mL water to obtain Solution A. 4.75 g of calciumchloride dihydrate was dissolved in 50 mL water to obtain Solution B.Both Solutions A and B were cooled to room temperature. Solution B wasadded to the alendronate-phosphate solution (Solution A), and themixture was mixed well to obtain Solution C. The pH of this clearSolution C was around 3.

1N sodium hydroxide and Solution C were simultaneously added to 300 mLof water at 40° C. while stirring, to keep the pH of the solution at6.75 at 40° C. until all the Solution C was added. The precipitate wascollected by filtration and washed with water. The solid was dried in anoven at 120° C. for more than 16 hours. 5.61 g of a calcium complex saltof alendronate and phosphate with a molecular ratio of 1:1 was thusobtained. Due to the presence of calcium phosphate, a complex orsosoloid of alendronate calcium-phosphate calcium (AC-PC) was generated.The active pharmaceutical ingredient (API) in the AC-PC complex isalendronate salt.

The same procedure was performed, but with varying molar ratios ofsodium alendronate and monobasic sodium phosphate, i.e. n=3, 5, 6, 8,10, 12, 15 and 20, to prepare complexes of AC-PC. The AC-PC complexeswith varying amounts of API are summarized in Table 1 below:

TABLE 1 Preparation of AC-PC Complex by Co-precipitation Molar ReactionCondition API % as solubility in saline** Ratio of TemperatureAlendronic in unit of in % times lower AC-PC* (° C.) pH acid mcg/mL byweight than Ca₃Y₂ 1:1 40 6.75 54.3 2.41  0.00024% 102 1:3 40 6.75 30.21.14  0.00011% 217 1:5 25 7.0 21.6 0.71 0.000071% 348 1:5 40 6.75 21.70.75 0.000075% 329 1:5 60 6.4 22.0 0.83 0.000083% 298 1:6 40 6.75 20.00.61 0.000061% 405 1:8 40 6.75 15.4 0.51 0.000051% 484  1:10 40 6.7512.6 0.44 0.000044% 558  1:10 65 8.0 12.7 0.54 0.000054% 457  1:12 406.75 11.3 0.35 0.000035% 714  1:15 40 6.75 9.1 0.31 0.000031% 797  1:2040 6.75 6.2 0.20 0.000020% 1235 *As the ratio of reactants: alendronatesodium vs. monobasic sodium phosphate **At room temperature and asalendronic acid.

The data in Table 1 shows that the solubility of the AC-PC complex, asalendronic acid, is surprisingly between 100 and 1200 times lower thanthat for alendronate calcium (AC) itself. For example, the solubility ofthe API in saline for an AC-PC complex with 12.6% API is only 0.44mcg/mL or 0.000044%, which is 558 times lower than that for alendronatecalcium, i.e. 247 mcg/mL, as reported in Comparative Example 1. Thisextremely low solubility of API for AC-PC complexes provides a base fora much better sustained release of the API. FIG. 1 demonstrates that theexperimental solubility of AC-PC complexes is uniformly reduced whilethe amount of API in the AC-PC complex decreases.

The reactions of the above co-precipitation methods to prepare AC-PCcomplexes may be performed under different conditions, such as differentpH values, temperatures, reactant mixing sequences, etc. However, theprofile for obtaining complexes with low solubility of the API remainsthe same.

EXAMPLE 2 Preparation of Complex of Risedronate Calcium and PhosphateCalcium (PC)

This example demonstrates that PC can also form complexes with calciumsalts of another bisphosphonate drug, risedronate calcium.

0.61 g (2 mM) anhydrous sodium risedronate and 2.4 g monobasic sodiumphosphate (anhydrous) were dissolved in 30 mL water. 5.6 g calciumchloride dihydrate were dissolved in 10 mL water. Therisedronate-phosphate solution and calcium chloride solution were mixedat room temperature.

The risedronate-calcium-phosphate solution and 0.5N sodium hydroxidewere simultaneously added to 100 mL water to maintain the pH at 7.00until all the risedronate had been added. The precipitate was collectedby filtration and washed with water. The solid was dried in an oven at105° C. 3.93 g of calcium complex salt of Risedronate with phosphatewere thus obtained.

Analysis indicates that the complex has an amount of the API (asrisedronic acid) of 12.33%. The solubility of the API (as risedronicacid) at room temperature in saline of this complex was 2.8 mcg/mL or0.00028%. This is a very low solubility and is suitable for sustainedrelease of the bisphosphonate drug.

EXAMPLE 3 Preparation of Complex of Zoledronate Calcium and PhosphateCalcium (PC)

This example demonstrates that PC can also form complexes with calciumsalts of another bisphosphonate drug, zoledronate calcium.

0.27 g (1 mM) zoledronic acid and 0.6 gm (5 mM) monobasic sodiumphosphate (anhydrous) were dissolved in 10 mL water. 1.5 g calciumchloride dihydrate was dissolved in 5 mL water. Thezoledronate-phosphate solution and calcium chloride solution were mixedat room temperature. 0.05 g calcium chloride dihydrate and 0.3 g sodiumchloride were added to 20 mL water. Sodium hydroxide andzoledronate-calcium-phosphate solution were simultaneously added to keepthe pH at 7.00 at room temperature until all the zoledronate-phosphatesolution was added. The precipitate was collected by filtration andwashed with water. The solid was dried in an oven at 120° C. 1.15 g ofcalcium complex salt of zoledronate with phosphate was thus obtained ina molecular ratio of 1:5.

Analysis indicates that this complex had an amount of API (as zoledronicacid) of 24.1%. The solubility at room temperature in water of thiscomplex, as zoledronic acid, was 7.5 mcg/mL or 0.00075%. This is a verylow solubility as well.

EXAMPLE 4 Preparation of Complex of AC and Pyrophosphate Calcium (PPC)

Pyrophosphate salt is also a common salt of pentavalent phosphorusoxoacid. This example demonstrates one exemplary method of preparing acomplex of Alendronate Calcium-Pyrophosphate Calcium (AC-PPC) byco-precipitation.

0.81 g sodium alendronate trihydrate and 1.12 g sodium pyrophosphatedecahydrate (Na₄P₂O₇·10H₂O) were dissolved in 75 mL water. 1.21 gcalcium chloride dihydrate was dissolved in 75 mL water. The temperatureof the alendronate-pyrophosphate solution was brought to 40 to 50° C.Calcium chloride and sodium hydroxide solutions were simultaneouslyadded to the alendronate-pyrophosphate solution while stirring to keepthe pH at 7.4 until all the calcium chloride solution was added. Themixture was cooled to room temperature. The precipitate was collected byfiltration and washed with water. The solid was dried in an oven at 105°C. overnight. 1.06 g of calcium complex salt of alendronate withpyrophosphate was thus obtained with a molecular ratio of 1:1.

Due to the presence of calcium pyrophosphate, a complex or sosoloid ofalendronate calcium and pyrophosphate calcium (AC-PPC) was generated.The same procedure as above was performed, but with varying molar ratiosof sodium alendronate and sodium pyrophosphate, i.e. n=2, 3, 5, and 10,to prepare more AC-PPC complexes. The AC-PPC complexes with varyingamounts of the API are summarized in Table 2 below:

TABLE 2 Preparation of AC-PPC Complex by Co-precipitation ReactionCondition API % as solubility in saline** Molar Ratio TemperatureAlendronic in unit of in % by of AC-PPC* (° C.) pH acid mcg/mL weight 150 7.4 36.7 18.2 0.00182% 2 40 7.4 28.4 5.3 0.00053% 3 50 7.4 19.8 3.90.00039% 5 50 7.4 14.4 0.8 0.00008% 10 50 7.4 7.9 0.4 0.00004% *As theratio or reactants: alendronate sodium vs. sodium pyrophosphate **Atroom temperature and as alendronic acid.The AC-PPC complex shows the same characterization for solubility of theAPI in saline as that for the AC-PC complex. Specifically, the AC-PPCcomplexes have very low solubility for the API, ranging from 0.00001% to0.001%. Also, the lower amount of the API in the complexes, the lowerthe solubility of the API.

EXAMPLE 5 Preparation of Complex of AC and Tripolyphosphonate Calcium(TPC)

This example demonstrates that calcium salts of another pentavalentphosphorus oxoacid, tripolyphosphonate, can also form a AlendronateCalcium-Tripolyphosphonate Calcium (AC-TPC) complex by co-precipitation.

2.03 g sodium alendronate trihydrate (6.25 mmol) and 6.9 g sodiumtripolyphosphate, Na₅P₃O₁₀ were added to 100 mL water, and the mixturewas stirred until all dissolved. 10.34 g calcium chloride dihydrate weredissolved in 200 mL water. The calcium chloride solution was heated to40° C. and the pH was adjusted to 7.0. Thealendronate-tripolyphosphonate solution was added into the calciumchloride solution dropwise, keeping the pH of the resulting solution at7.0 by adding 1N NaOH. The precipitate was collected by filtration andwashed with water. The solid was dried in an oven at 120° C. overnight.8.82 g of calcium complex salt of alendronate with tripolyphosphate wasthus obtained.

Analysis indicates that this complex has 12.6% API, as alendronic acid.The solubility of the API (as alendronic acid) in saline at roomtemperature for this complex was 2.69 mcg/mL or 0.000269%. Therefore,AC-TPC is also a complex with very low solubility of the API.

EXAMPLE 6 Preparation of Complex of Alendronate Zinc-Phosphate Zinc

The metal in the AC-PC complex can be replaced by other divalent metalssuch as zinc, magnesium, etc. This example demonstrates preparation ofcomplexes of alendronate zinc-phosphate zinc by co-precipitation.

3.25 g of sodium alendronate trihydrate and 1.42 g of dibasic sodiumphosphate (anhydrous) were dissolved in 100 mL water. The solutiontemperature was kept at 50° C. on a hot plate. This temperature wasmaintained throughout the process. While stirring, a solution of 5.8 gof zinc acetate dihydrate in 50 mL of water was added to thealendronate-phosphate solution. The pH of the solution was kept at 7.4by adding sodium hydroxide solution simultaneously until all the zincacetate solution was added. The precipitate was collected by filtrationand washed with water. The solid was then dried at 120° C. overnight.5.28 g of zinc complex salt of alendronate and phosphate with amolecular ratio of 1:1 was thus obtained. The solubility of the API (asalendronic acid) in saline at room temperature for this complex is 2.4mcg/mL, i.e. 0.00024%. It also has a very low solubility of the API.

EXAMPLE 7 Preparation of AC-PC Complex by Adsorption

Besides the co-precipitation method, the AC-PC complexes can be preparedby various other methods, such as, for example, adsorption anddiffusion. In this example, a commercial hydroxyapatite (HA), which isone of various forms of phosphate calcium, is used to prepare an AC-PCcomplex by adsorption.

0.66 g (2.0 mM) sodium alendronate trihydrate was added to 50 mL water,and the solution was stirred until all dissolved. The pH was adjusted tothe range of 8.0 to 8.5. 2 g of hydroxyapatite (Spectrum, CA165) wasadded and the solution was stirred at room temperature for 20 hr. Afterstirring, 200 mL of water was added and the solid was separated byfiltration. The solid was transferred, 200 mL of water was added, andthe solid was filtered again. This process was repeated one more time.The solid product was dried at 105° C. for more than 3 hrs. The complexhad 8.8% API, as alendronate acid, and its solubility of the API at roomtemperature in saline was 7.9 mcg/mL, or 0.00079%.

EXPERIMENTAL EXAMPLE 1 Pharmacokinetic (PK) Study of AC-PC Complex onRat Model

In this study, the AC-PC complex with 12.6% API prepared in Example 1was intramuscularly injected into Group A female Sprague-Dawley rats(n_(A)=12). The age of the female rats was about 4 months. Each rat wasinjected with 8 mg of the AC-PC complex, which contains 1 mg of API (asalendronic acid). The PK profile for long-term sustained release wasstudied through urine excretion of alendronate. Urine samples werecollected over 24 hour intervals. The alendronate from the AC-PC complexexcreted in the urine was first precipitated by calcium phosphateco-precipitation, then derivatized by 2,3-naphthalenedialdehyde, anddetermined by reverse phase high performance liquid chromatography(HPLC) equipped with a fluorescence detector.

A prior art active control, alendronate calcium, prepared in ComparativeExample 1, was used in this PK study in Group B female rats (n_(B)=10).The active control had a solubility of API in saline of 404 mcg/mL or0.0404%, which is much higher than that for the AC-PC complexes ofExample 1. Table 3 summarizes the daily urine excretion of alendronate,as alendronic acid, after the administration of the AC-PC complex ofExample 1 and the active control.

FIG. 2 gives the curve of rat urine daily excretion versus the number ofdays after administration for both the AC-PC complex of Example 1 (bluecurve) and the active control of the prior art (red curve). The figuredemonstrates that the complexes according to certain embodiments of thisinvention can provide significantly better and longer sustained releaseeffects than the prior art.

TABLE 3 Daily Rat Urine Excretion of Alendronate Days after Prior ArtThis Invention administration mcg/day mcg/day 0 0.1 0.0 1 73.5 6.7 317.5 5.1 5 16.7 4.7 7 7.5 6.5 10 5.5 7.4 13 8.3 16 1.4 17 7.1 21 5.8 230.5 25 4.2 30 2.8 35 1.8 42 1.3 49 0.8 56 0.5 63 0.3 70 0.2As summarized by Table 4 below, the two products, AC-PC complexes ofthis invention and the prior art (AC only) were studied with the sameanimal model (rat), at the same dose (1 mg per rat) and demonstrated thesame amount of total excretion. The tested compositions of thisinvention (AC-PC complexes) showed much better sustained releaseeffects, as discussed below:

(1) Initial Bolus: 7 Times Lower

Initial bolus is defined as the percentage of the amount released in thefirst 3 days based on the total released amount. For a sustainedrelease, small initial bolus is desired to reduce overdose and to avoidthe surge of possible adverse effects caused by a high initial bolus.Certain embodiments of this invention release only 8% of total releaseddrug in the first 3 days (measured by rat urine excretion). However, theprior art product releases 55% of total released drug during the sameperiod, i.e. more than half of the drug is released in the first 3 days.Therefore, the initial bolus for certain embodiments of this inventionis seven (7) times lower than that for the prior art.

(2) Cmax: 9 Times Lower

Sustained release avoids high peak amounts of the drugs in the humanbody. The peak amount is denoted Cmax. A good sustained release drugshould have lower Cmax to reduce possible toxicity and adverse effectscaused by a high Cmax. This example used urine excretion as theindication of sustained release. Cmax corresponds to the maximum dailyurine excretion, which measured 74 mcg/day for the prior art and 8mcg/day for the tested complexes of this invention. Namely, certainembodiments of this invention have a Cmax nine (9) times lower than theproduct of the prior art.

(3) Tmax: 13 Times Delayed

The time when Cmax appears is defined as tmax. Long-term sustainedrelease drugs might also have a delayed tmax. The tmax was 1 day for theprior art and 13 days for the tested complexes of this invention.Namely, certain embodiments of the present invention have a tmaxthirteen (13) times more delayed than the product of the prior art.

TABLE 4 A Comparison of Sustained Release Parameters This Advantage ofItems Prior Art Invention This Invention Model Rats Rats AdministrationIM IM # of Rats 10 12 Dose, mg 1000 1000 the same Total Excretion 230210 the same Total Net Bone Absorbed 770 790 the same Net BoneAbsorption Rate, % 77% 79% the same Initial Bolus (in the first3 55%  8%7 times lower days), % of Released Drug C_(max) for Released Drug 74 8 9times lower (Daily Excretion) tmax for Released Drug 1 13 13 timeslonger Number of days to release 2.8 16.6 6 times longer 50% of APIduration Number of days to release 9.0 38.5 4 times longer 90% of APIduration

(4) Number of Days to Release 50% of the Drug: 6 Times Longer

The effect of a sustained release drug can be characterized by thenumber of days it takes to release 50% of the drug, which may be denotedas N₅₀. Long-term sustained release drugs should have a longer N₅₀. TheN₅₀ was 2.8 days for the prior art and 16.6 days for the testedcompositions of this invention. Thus, certain embodiments of thisinvention have a N₅₀ six (6) times longer than the product of the priorart.

(5) Number of Days to Release 90% of the Drug: 4 Times Longer

The effect of a sustained release of a drug can also be characterized bythe number of days it takes to release 90% of the drug, which may bedenoted as N₉₀. A long-term sustained release drug should have a longerN₉₀. The N₉₀ was 9.0 days for the prior art product and 38.5 days forthe tested compositions of this invention. Thus, certain embodiments ofthis invention have a N₉₀ four (4) times longer than the product of theprior art.

EXPIREMENTAL EXAMPLE 2 Efficacy Study of AC-PC Complex on Rat Model

This Experimental Example demonstrates the efficacy of long-termsustained release of certain AC-PC complexes of this invention. In thisstudy, the AC-PC complex formulations were intramuscularly injected intofemale Sprague-Dawley rats. Rats used in this study underwentoveriectomy operations (OVX). The age of the female rats was around 2½months when the surgical operation was performed. A 2½-month recoveryperiod was allowed after overiectomy/sham operations to ensurepost-surgical recovery and to establish hypoestrogenemia andosteoporosis before treatment with the AC-PC complexes.

The rats were divided into three (3) groups:

Group-A: treated by AC-PC complexes at lower doses, 0.25 mg (alendronicacid)

Group-B: treated by AC-PC complexes at higher doses, 1.0 mg (alendronicacid)

Group-C: treated by placebos (saline)

The treatment drugs or placebos (saline) were injected once every 2months. Three injections were administrated at 0, 60 and 120 days.

The AC-PC complexes used in this Example had 12.6% of the API and wereprepared as in Example 1. The bone-preserving effects of the complexwere measured as percent change in bone mineral density (BMD) by DualX-Ray Absorptiometry (DEXA) in the right femur 4.3 mm from the proximalend in an area of 8.6×7.2 mm. The BMD for all rats was measured at day0, 7, 14, 28, 35, 42, 49, 56, 90, 120, 135, 150, 165 and 180. Theobtained data is summarized in Table 5 and FIG. 3.

TABLE 5 Mean BMD Change, Right Femur of OVX Rats Rat Group A B C Type ofRats OVX OVX OVX Treatment Saline AC-PC complex AC-PC complex Dose, mg,as alendronic acid Placebo 0.25 × 3 1 × 3 Items Mean S.D. Mean S.D. MeanS.D. Measured 0 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% at Days 7 0.3% 1.4% 0.2%1.7% 0.3% 1.0% after 14 −1.8% 2.3% 2.5% 2.3% 1.1% 1.6% administration 21−0.9% 2.2% 3.6% 2.3% 2.9% 1.2% 28 −1.0% 2.8% 3.6% 2.5% 2.9% 1.9% 35−1.5% 2.6% 4.4% 2.6% 3.9% 1.9% 42 −1.2% 3.1% 3.8% 3.1% 4.5% 2.3% 49−2.2% 2.8% 4.2% 3.2% 3.6% 1.8% 56 −2.4% 3.0% 5.1% 2.6% 4.4% 1.7% 90−1.5% 3.8% 5.7% 2.1% 5.9% 1.8% 120 −2.3% 3.7% 5.5% 3.2% 6.4% 2.3% 135−2.5% 2.9% 6.4% 3.1% 7.3% 2.3% 150 −2.8% 2.6% 6.6% 4.2% 8.4% 2.4% 165−2.7% 3.1% 6.3% 3.2% 9.0% 2.2% 180 −3.0% 2.8% 6.8% 3.6% 9.4% 2.5%The AUC_(0.180) (area under curve) for all 3 rat groups are summarizedin Table 6 below. The p-value for efficacy is evaluated with placebogroup (Group C). All p-values are significantly less than 0.05, whichconfirmed the efficacy of the tested complex for osteoporosis throughlong-term sustained release.

TABLE 6 Efficacy of Long-term Sustained Release Complex TypeAUC_(0,180)*, Dose of Rat # of %-day p-value Treatment mg/Rat Rats GroupRats n Mean S.D vs. A Placebo: — OVX A 12 −3.5 4.8 — Saline AC- 0.25 × 3OVX B 12 9.1 4.5 <0.0001 CDHA AC-   1 × 3 OVX C 12 10.0 2.9 <0.0001 CDHA*Negative AUC indicates decrease in BMD over time.

EXPERIMENTAL EXAMPLE 3 Evaluation of Tissue Tolerance (TT) of AC-PCComplex by Rat Model

The objective of this Example is to evaluate the local tissue tolerance,and both macroscopic and microscopic (histopathological) examination oftissue toxicity/reaction of AC-PC complexes were performed.

Bisphosphonate salt can cause tissue damage and irritation followingintramuscular injection. However, the solubility of bisphosphonate forAC-PC complexes according to certain embodiments of this invention isreduced by 100 to 1000 times compared to alendronate calcium accordingto the prior art. Therefore, the tissue tolerance level for AC-PCcomplexes may reach the same level that is acceptable for the FDA andpatients.

(1) Study Procedure

The AC-PC complexes, with 12.6% API, prepared as in Example 1, was usedfor tissue tolerance evaluation by a rat model. 0.9% saline was used asa negative control. A medroxyprogesterone acetate (MPA) suspensioninjection (150 mg/mL) (which is an FDA approved sustained release drug)was used as a reference control.

A total of 70 rats were used in this study. Thirty five (35) rats,assigned in Group T, were intramuscularly (IM) injected with 0.25 mL ofthe AC-PC complex in the right thigh and with 0.25 mL of 0.9% saline inthe left thigh. Another 35 rats, assigned in Group R, were IM injectedwith 0.25 mL MPA (the reference control) in the right thigh. Rats wereexamined for general health conditions prior to injection on Day 0. Alltissue response evaluations were performed at 1, 7, 14, 28, 56, 84, and120 days post injection. Five (5) rats from each group (T and R) weresacrificed at each post injection time point listed above.

(2) Macroscopic Edema and Erythema Examination

Macroscopic examinations of the treatment sites for evidence of anytissue reaction such as erythema and edema were performed. The edema anderythema scoring system was adapted from USP <88> Biological ReactivityTests, in vivo.

To evaluate macroscopic edema and erythema, Mean Tissue Reaction Score(MTRS) was used. The MTRS is the average of all edema and erythemascores. MTRS for all three (3) treatments at 7 evaluation points arelisted in Table 7 below.

As shown in Table 7, throughout the study period, the macroscopic edemaand erythema evaluations identified little to no tissue irritationobserved for the AC-PC complex and the reference control MPA as well asthe negative control. The macroscopic MTRS score for the AC-PC complexwas zero (0) indicating it is a non-irritant drug through out the120-day study period with respect to edema and erythema.

TABLE 7 Summary of Mean Tissue Reaction Scores (MTRS) Post # of RatsSaline, MPA, Injection in groups AC-PC Complex Negative ControlReference Control Day T & R Edema Erythema Edema Erythema Edema ErythemaDay 1 35 0 0 0 0 0 0 Day 7 30 0 0 0 0 0 0 Day 14 25 0 0 0 0 0 0 Day 2820 0 0 0 0 0 0 Day 56 15 0 0 0 0 0 0 Day 84 10 0 0 0 0 0 0 Day 120 5 0 00 0 0 0 Macroscopic MTRS 0 0 0 Score: 0—None, 1—Slight, 2—Well-defined,3—Moderate, 4—Severe

(3) Microscopic Histopathological Examination

Microscopic evaluation was performed using a 0 through 4 grading systemthat fulfills the biologically relevant aspects of ASTM F 981 (2004) andISO 10993-6:1994 (E) guidelines.

The mean histopathological examination score (MHES) was calculated usingan average of all five (5) tissue histopathological examination scoresat the same post injection date. The MHESs for all three (3) treatmentsat 7 evaluation points are listed in Table 8 below.

TABLE 8 Summary of Mean Histopathological Examination Score* (MHES) PostAC-PC Saline Difference Injection Complex Negative Between T Day (T)Control MPA (R) and R, T − R 1 8.8 2.8 10.5 −1.7 7 7.4 1.6 8.8 −1.4 1412.0 0.6 9.6 2.4 28 16.2 0.6 13.6 2.6 56 12.2 0 7.4 4.8 84 7.6 0 8.5−0.9 120 5.6 0 8.8 −2.1 *Scale for Conclusion: Nonirritant (0.0-2.9),Slight Irritant (3.0-8.9), Moderate Irritant (9.0-15.0), Severe Irritant(≧15.1)As shown in Table 8, the microscopic histopathological examinationscores for the AC-PC complex were very similar to those for theReference Control and MPA over time. Since the MHESs decreased overtime, resorption of the AC-PC complex with corresponding diminution ofthe inflammatory reaction with time was likely.

(4) Conclusion for Tissue Tolerance

In summary, based on both macroscopic and microscopic evaluation, theAC-PC complexes according to certain embodiments of the presentinvention may be associated with an acceptable level of tissue toleranceas compared to the commercially and clinically available ReferenceControl (MPA).

The examples and experiments described above are presented solely forillustrative purposes and are not meant to limit the scope of theinvention in any way. While the invention has been described withreference to certain exemplary embodiments, it is understood that theinvention is not limited to the described embodiments since those ofordinary skill in the art would recognize that many changes andmodifications may be made to the described embodiments without departingfrom the spirit and scope of the invention, as defined in the appendedclaims.

What is claimed is:
 1. A pharmaceutical composition comprising: anamorphous sosoloid comprising: a salt of a bisphosphonate drug; and asalt of a pentavalent phosphorus oxoacid.
 2. The pharmaceuticalcomposition according to claim 1, wherein the salt of the bisphosphonatedrug is present in an amount of less than about 50% by weight based onthe total weight of the amorphous sosoloid.
 3. The pharmaceuticalcomposition according to claim 1, wherein the bisphosphonate drugcomprises a compound represented by (HO)₂PO—R—OP(OH)₂, wherein thechemical composition of the functional group R dictates thebisphosphonate drug as pamidronic acid, alendronic acid, ibandronicacid, risedronic acid, zoledronic acid or tiludronic acid.
 4. Thepharmaceutical composition according to claim 1, wherein the salt of thebisphosphonate drug comprises a salt selected from the group consistingof: normal salts, acidic salts, basic salts and combinations thereof;calcium salts, zinc salts, magnesium salts, and combinations thereof;and anhydrous salts, hydrates and combinations of hydrates.
 5. Thepharmaceutical composition according to claim 4, wherein a weight ratioof metal to phosphorus ranges from about 0.5 to about 3.0.
 6. Thepharmaceutical composition according to claim 1, wherein the salt of thepentavalent phosphorus oxoacid comprises a salt selected from the groupconsisting of: normal salts, acidic salts, basic salts and combinationsthereof; calcium salts, zinc salts, magnesium salts, and combinationsthereof; phosphates, pyrophosphates, metaphosphates, polyphosphates andcombinations thereof; and anhydrous salts, hydrates and combinations ofhydrates.
 7. The pharmaceutical composition of claim 6, wherein the saltof the pentavalent phosphorus oxoacid is selected from the groupconsisting of dicalcium phosphate dihydrate, dicalcium phosphateanhydrate, octacalcium phosphate, α-tricalcium phosphate, β-tricalciumphosphate, amorphous calcium phosphate, calcium-deficienthydroxyapatite, hydroxyapatite, and tetracalcium phosphate.
 8. Thepharmaceutical composition according to claim 1 wherein, wherein theamorphous sosoloid has an average particle size of less than about 100micrometers.
 9. The pharmaceutical composition according to claim 1,wherein the amorphous sosoloid suspended in an aqueous medium to form anaqueous suspension.
 10. The pharmaceutical composition according toclaim 9, wherein the aqueous suspension has a pH ranging from about 6.0to about 9.5.
 11. The pharmaceutical composition according to claim 1,wherein the amorphous sosoloid has a solubility in saline of less thanabout 0.05% by weight as bisphosphonic acid.
 12. The pharmaceuticalcomposition according to claim 1, further comprising at least oneinactive pharmaceutical excipient.
 13. The pharmaceutical compositionaccording to claim 12, wherein the inactive pharmaceutical excipient isselected from the group consisting of surfactants, suspending agents,dispersing agents, tonicity agents, preservatives, pH buffers, agentsfor adjusting osmotic pressure, agents for adjusting viscosity andagents for adjusting density.
 14. A pharmaceutical compositioncomprising an aqueous suspension of an amorphous sosoloid, the amorphoussosoloid comprising: a calcium salt of a bisphosphonate drug; and acalcium salt of a pentavalent phosphorus oxoacid.
 15. The pharmaceuticalcomposition according to claim 14, wherein the calcium salt of thebisphosphonate drug is present in an amount of less than about 50% byweight based on the total weight of the amorphous sosoloid.
 16. Thepharmaceutical composition according to claim 14, wherein the amorphoussosoloid has an average particle size ranging from about 1 to about 100micrometers.
 17. The pharmaceutical composition according to claim 14,wherein the aqueous suspension of the amorphous sosoloid has a pHranging from about 6.0 to about 9.5.
 18. The pharmaceutical compositionaccording to claim 14, wherein a weight ratio of calcium to phosphorusranges from about 0.5 to about 3.0.
 19. The pharmaceutical compositionaccording to claim 14, wherein the amorphous sosoloid has a solubilityin saline of less than about 0.05% by weight as bisphosphonic acid.